Conference presentation
Updated experience of abacavir hypersensitivity genetic testing within the major histocompatibility complex (MHC): addressing diagnostic precision and predictive value
5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV (Paris, France, 08/07/2003–11/07/2003)
2003
Abstract
OBJECTIVES: To assess the predictive value (PV) of genetic testing for abacavir hypersensitivity syndrome (HSR) in the Western Australian HIV Cohort Study, and to extend genetic mapping of genetic susceptibility locus/loci. Abacavir-specific immunological responses were assessed to improve precision of the HSR diagnostic classification, and to provide insights into possible underlying mechanisms.
METHODS: The abacavir-exposed cohort comprised prospectively tested patients (n=48) and retrospectively analysed abacavir-exposed individuals (n=200). Diagnostic precision was assessed using epicutaneous patch testing, and immunological response to ex vivo abacavir exposure measured by peripheral blood mononuclear cell tumour necrosis factor alpha (TNF-α) expression (three-colour flow cytometry) or whole blood extracellular TNF-α (chemiluminescence). Depletion of CD4 and CD8 cells was undertaken to determine the characteristics of the major histocompatibility complex (MHC)-restricted immune response. MHC typing utilized standard molecular techniques, and genetic mapping within the MHC Class III region analysed single nucleotide polymorphisms (SNP) to identify recombinant MHC haplotypes.
RESULTS: Application of revised diagnostic criteria (including a positive ex vivo test) identified abacavir HSR 18 cases out of 248 abacavir-exposed patients (2/48 prospectively tested). HLA-B*5701 was present in 94% of cases and 1.7% of controls (OR 587, PV+ 81%, PV– 99.6%). Based on these data, prospective testing for HLA-B*5701 carriage would be predicted to reduce abacavir HSR incidence from 7.3% to 0.4%, while inappropriately denying 1.6% of the population access to abacavir. Presence of HLA-B*5701 and a central MHC polymorphism (hspA1L rs2227956C) was found in 94% of cases and 0.43% of controls (OR 3910, PV+ 94%, PV– 99.5%). Depletion of CD8 cells resulted in marked attenuation of abacavir-stimulated TNF-α expression ex vivo, consistent with a Class I-restricted immune response. Recombinant mapping in patients carrying markers of the 57.1 ancestral/extended haplotype suggest a susceptibility locus within the highly conserved heat shock protein 70 (hsp70) gene cluster, although these data suggest that the HLA-B*5701 may provide specificity to the abacavir-induced immune response.
CONCLUSION: Presence of HLA-B*5701 is highly predictive of abacavir HSR in the Western Australian HIV Cohort, with evidence that an abacavir-specific Class I-restricted immune response may involve the concurrence of HLA-B*5701 and a second locus within the central MHC that is carried on the 57.1 extended haplotype.
Details
- Title
- Updated experience of abacavir hypersensitivity genetic testing within the major histocompatibility complex (MHC): addressing diagnostic precision and predictive value
- Authors/Creators
- A. Martin (Author/Creator)D. Nolan (Author/Creator)S. Gaudieri (Author/Creator)C. Almeida (Author/Creator)F. Carvalho (Author/Creator)C. Witt (Author/Creator)D. Sayer (Author/Creator)R. Nolan (Author/Creator)S. Herrmann (Author/Creator)F. Christiansen (Author/Creator)S. Mallal (Author/Creator)
- Conference
- 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV (Paris, France, 08/07/2003–11/07/2003)
- Identifiers
- 991005544402707891
- Murdoch Affiliation
- Centre for Clinical Immunology and Biomedical Statistics
- Language
- English
- Resource Type
- Conference presentation
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